Pleiotropic effects of candidate genes on autism spectrum disorder and comorbidities: genetics, funcional studies and animal models
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social communication and interaction, as well as repetitive and restricted patterns of behaviour. Although growing evidence supports a main contribution of genetic factors to its neurobiology and hundreds...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2021 |
| País: | España |
| Institución: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/673823 |
| Acceso en línea: | http://hdl.handle.net/10803/673823 |
| Access Level: | acceso abierto |
| Palabra clave: | Autisme Autismo Autism Genètica mèdica Genética médica Medical genetics Neurociències Neurociencias Neurosciences Anomalies cromosòmiques Anomalías cromosómicas Chromosome abnormalities Models animals en la investigació Modelos animales en investigación Animal models in research Ciències Experimentals i Matemàtiques 575 |
| Sumario: | Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social communication and interaction, as well as repetitive and restricted patterns of behaviour. Although growing evidence supports a main contribution of genetic factors to its neurobiology and hundreds of candidate genes have been identified in recent years, the genetic architecture of the disorder is still not fully understood. Moreover, ASD frequently co-occurs with other developmental and psychiatric disorders, and shared genetic mechanisms are hypothesized to underlie these comorbidities. In this doctoral thesis, we aimed to study the contribution of several candidate genes to ASD and comorbidities. We have focused on the 14-3-3 gene family, RBFOX1 and the BEX/TCEAL gene family, performed genetic and functional studies and further characterized the neurobiological effects of their deficiency using animal models. First, our results suggest a role for the 14-3-3 genes in ASD and schizophrenia (SCZ). Ultra-rare variants in the 14-3-3 genes are enriched in ASD and common and rare variants in the YWHAE and YWHAZ genes, respectively, are associated with SCZ. We have also reported alterations in the expression of these genes in postmortem brains of ASD or SCZ patients. Furthermore, we have demonstrated a loss-of-function effect of a damaging variant in the YWHAZ gene present in two siblings with ASD and attention deficit/hyperactivity disorder (ADHD). In addition, we have characterized ywhaz expression in zebrafish across development and in adulthood and demonstrated that ywhaz depletion causes alterations in behaviour, in neuronal activity and connectivity and in monoamine signalling. The behavioural changes included freezing and were rescued with drug treatments that target monoamine neurotransmission. Second, we have demonstrated a relevant contribution of common variants in RBFOX1 to psychiatric disorders and traits. Also, we have shown that a high number of copy number variants (CNVs) spanning RBFOX1 are reported in patients with psychiatric conditions, the vast majority in patients with ASD or SCZ, and patients with these disorders also show a decreased expression of RBFOX1 in cortex. Finally, we have used knockout animal models to understand its role in psychiatric disorders, and demonstrated that both mice and zebrafish RBFOX1- deficient models present behavioural alterations that can be related to neurodevelopmental disorders such as ASD, ADHD and SCZ. Third, we found that all BEX/TCEAL genes are downregulated in postmortem brain regions of ASD and SCZ patients and that rare CNVs spanning several BEX/TCEAL genes have been reported in patients with severe neurodevelopmental problems. Furthermore, Bex3-deficient mice show anatomical and molecular alterations in brain, an excitatory/inhibitory imbalance and behavioural alterations that can be assimilated to ASD- and SCZ-like symptoms. |
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